Rheumatoid arthritis (RA) is a chronic disease involving painful destruction of the joints and eventual loss of function. Although its etiology remains unknown, genetic and experimental data strongly suggest deleterious CD4+ T cell responses drive the pathogenesis of RA. Current treatment strategies aimed at modifying late- stage consequences of inflammation do not correct underlying T cell defects and are therefore not curative. Thus, a better understanding of intrinsic regulatory factors of arthritogenic T cells is warranted. The proposed CDA, which encompasses hypothesis-driven research coupled with a multi-disciplinary training plan, will enable me to reach my ultimate goal of integrating my prior training in host-directed therapeutics (HDT) with my knowledge of biological processes that drive immunity, allowing me to advance new treatments for veterans suffering from RA. My prior PhD training in the fields of microbial infection and HDT coupled with recent post- doctoral training in translational medicine and preclinical animal models of arthritis have provided me with a solid foundation upon which to build novel studies proposed in this application. I have gathered key preliminary data in a preclinical model of RA (SKG mice) that supports the premise of this application; that NOD2 functions as an endogenous negative regulator of TCR-mediated activation and pro-inflammatory responses of CD4+ T cells in RA. The major goals of this application are to investigate how NOD2 controls TCR-mediated activation and function of CD4+ T cells in RA (Aim1), and to elucidate how expression of NOD2 suppresses the pathogenicity and alters the gene expression profile of a discrete subset of arthritogenic CD4+ T cells in SKG mice (Aim2). Completion of this work will provide important mechanistic insight regarding the function of NOD2 in T cells from RA patients as well as reveal additional molecular pathways independent of NOD2 that control arthritogenic T cell responses. Results from these studies will tell us whether we might be able to reprogram aberrant T cells to stop inflammation and irreversible joint damage in RA patients. This study will serve as a platform for future work in manipulation of TCR-signaling responses in RA. To gain clinical and laboratory skills needed for this project, and to attain my goal of becoming an independent translational investigator at the VA Portland Healthcare System (VAPORHCS), I have developed a training plan consisting of didactic coursework, conferences, and laboratory experience that will be guided by an expert multidisciplinary mentoring team. The VAPORHCS is a national leader in research with over 100 investigators and over 500 active research proposals with an excellent track record of training junior investigators. The strong collaborative relationship between VAPORHCS and the affiliated hospital and research center, Oregon Health & Science University (OHSU), will allow me further access to collaborators, educational opportunities and core resources that are instrumental to the success of this application. I have the full support of my entire mentoring team to pursue the results of the proposed research topics for submission of a Merit application and in transition to a junior faculty member. My long-term career goal is to become an independent scientist at the VAPORHCS with a translational research program focused on understanding factors that regulate CD4+ T cell responses in RA that may be molded into future T cell-targeted therapeutics.